6-APB was first synthesized in 1993 by David E. Nichols as a potential non-neurotoxic alternative to MDMA.[1] However, it did not come into popular recreational use until over a decade later, where it briefly entered the rave scene and global research chemicals market. It was sold along with other novel benzofuran entactogens under the name "Benzofury" before its sale and import were subsequently banned.[citation needed]

Very little data exists about the pharmacological properties, metabolism, and toxicity of 6-APB, and it has only a brief history of human usage. It has been marketed alongside research chemicalentactogens like 5-MAPB and 5-APB as a legal, grey-market alternative to MDMA, and is typically commercially distributed by online research chemical vendors. It is highly advised to use harm reduction practices if using this substance.

History and culture

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The synthesis of 6-APB was first reported by a team led by the medicinal chemist and psychedelic researcher David E. Nichols at Purdue University. They were examining the role of the MDA dioxle ring structure in interacting with serotonergic neurons. It was also partly an effort to find an alternative to MDMA, which was gaining recognition as a potentially useful adjunct in psychotherapy, but was also being linked to neurotoxic effects.[1]

Human usage was not documented until 2010, when it emerged for sale on the research chemical market. It was particularly prominent in the UK "legal highs" market, where it was sold under the name "Benzofury".[citation needed]

On June 10, 2013 6-APB and a number of analogues were classified as Temporary Class Drugs in the UK following an ACMD recommendation.[2] On November 28, 2013 the ACMD recommended that 6-APB and related benzofurans should become Class B, Schedule 1 substances. On March 5, 2014 the UK Home Office announced that 6-APB would be made a class B drug on 10 June 2014 alongside every other benzofuran entactogen and many structurally related drugs.[3]

Chemistry

6-APB, also known as 6-(2-aminopropyl)benzofuran, is a synthetic molecule of the benzofuran class. The benzofuran class of substances are members of the amphetamine and phenylethylamine classes. Molecules of this class contain a phenethylamine core bound to an amino (NH2) group through an ethyl chain with an additional methyl substitution at Rα. 6-APB does not contain a methyl substitution on RN. It is composed of an an oxygen-substituted benzofuran ring fused at R3 and R4 of the phenyl ring.

Notably, 6-APB shares this benzofuran ring with related compounds such as 5-APB, 5-MAPB, and 6-MAPB.

Three distinct batches have been in circulation since its initial release to markets. Originally, only hydrochloride was available, and its dosage range shared characteristics most similar to that of MDA in terms of dose-response. However, succinate and fumarate batches both entered the market, and have very different effects by weight, and vastly different loose bulk densities.[citation needed]

6-APB is a potent full agonist of the serotonin 5-HT2B receptor (Ki = 3.7 nM)[4], with higher affinity for this target than any other site.[6] Moreover, unlike MDMA, 6-APB shows 100-fold selectivity for the 5-HT2B receptor over the 5-HT2A and 5-HT2C receptors.[6][7]

Aside from the 5-HT2B receptor, 6-APB has also been found to bind with high affinity to the α2C-adrenergic receptor subtype (Ki = 45 nM), although the clinical significance of this action is unknown.[4]

The potent agonism of the 5-HT2B receptor makes it likely that 6-APB would be cardiotoxic with chronic or long-term use, as seen with other 5-HT2B receptor agonists such as the withdrawn serotonergic anorectic fenfluramine.[4][8]

The monoamine neurotransmitters known as serotonin, dopamine and noradrenaline are the global neurotransmitters that modulate the brain's ability to feel pleasure, motivation, reward, planning, attention, and focus. When their reuptake is inhibited or their release is promoted, these neurotransmitters accumulate in the synaptic cleft (gaps between neurons) to non-ordinary levels, which makes them able to be reused. The result is neuronal activation at a multitude of brain regions which has the net result of producing a combination of stimulating, relaxing, disinhibiting and euphoric effects.[9]

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWikicontributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects

Stimulation & Sedation - In terms of its effects on the user's physical energy levels, 6-APB is commonly considered to have the paradoxical ability to both be stimulating as well as sedating and relaxing. Overall, it is thought to be far less energetic than MDMA or MDA and tends to exert more of a pronounced "stoning" or "couch-locking" effect. The particular style of stimulation which 6-APB presents is far less forceful in a way that can be compared to psychedelics like mescaline.

Spontaneous physical sensations - The "body high" of 6-APB can be described as a moderate to powerful warm, euphoric tingling sensation that radiates throughout the entire body. It is capable of becoming overwhelmingly pleasurable at higher doses to the point of immobilizing the user. This sensation maintains a consistent presence that steadily rises with the onset and hits its limit once the peak has been reached.

Increased bodily temperature - As 6-APB is a serotonin releasing agent, a rise in core body and brain temperature tends to be high and consistent throughout the experience. Caution must be taken as too high of a dose can result in the dysregulation of the brain's ability to regulate its internal core temperature. 6-APB is commonly reported to having a similar hyperthermia to MDA and MDMA, but slightly warmer than either. Serotonin syndrome, a potentially fatal condition, presents this effect to dangerous levels.

Vibrating vision - At common to high doses, a person's eyeballs may begin to spontaneously wiggle back and forth in a rapid motion, causing the vision to become blurry and temporarily out of focus. This is a condition known as nystagmus.

Dehydration - Feelings of dry mouth and dehydration are a universal experience with this class of compounds; this effect is a product of an increased heart rate and bodily metabolism. While it is important to avoid becoming dehydrated (especially when out dancing in a hot environment) there have been some notable cases of users suffering from water intoxication through over-drinking (to compensate). It is therefore advised that users be mindful of their water intake and avoid over-drinking.

Difficulty urinating - Higher doses of 6-APB can result in an overall difficulty when it comes to urination. This is an effect that is completely temporary and harmless. It is due to 6-APB’s promotion of the release of anti-diuretic hormone (ADH); ADH is responsible for regulating urination. This effect can be lessened by simply relaxing, but can be significantly relieved by placing a hot flannel over the genitals to warm them up and encourage blood flow to the region.

Teeth grinding - This is usually only present at moderate to higher doses and is similar to what one might experience from MDMA or MDA.

Seizure - This is a rare effect but are thought to be able to occur in those who are predisposed to them, especially when taking overly strong doses or redosing while in physically taxing conditions such as being dehydrated, fatigued, undernourished, or overheated.[citation needed]

Visual effects

The visual effects of 6-APB have an occurrence rating that is more selective and less consistent than any of the traditional psychedelics. The effects can never be guaranteed to manifest themselves, but are the most likely to occur with high doses, towards the end of the experience and particularly if the user has been smoking cannabis. They are also more likely to occur if the user has prior experience with psychedelics, but also remain entirely possible for those who have never tried them as well.

Enhancements

6-APB presents an array of visual enhancements which are mild in comparison to traditional psychedelics, but still distinctively present. These generally include:

Color enhancement - The enhancement can be described as bright and synthetic in appearance, and consistent throughout the experience.

Distortions

The visual geometry of 6-APB experience can be described as more similar in appearance to that of mescaline than LSD or psilocin. It can be comprehensively described through its variations as primarily intricate in complexity, abstract in form, organic in style, structured in organization, dimly lit in lighting, mostly monotone in color with blues and greys, glossy in shading, sharp in edges, small in size, fast in speed, smooth in motion, equal in round and angular corners, non-immersive in-depth and consistent in intensity. At higher doses, they are significantly more likely to result in states of level 8A visual geometry over level 8B.

Hallucinatory states

At high to heavy doses, 6-APB is capable of producing a unique range of low and high-level hallucinatory states in a fashion that is significantly less consistent and reproducible than that of many other commonly used psychedelics. These effects are far more common during the offset of the experience and commonly include:

External hallucination (autonomous entities; settings, sceneries, and landscapes; perspective hallucinations and scenarios and plots) - This effect is very similar to the same experience found within deliriants, but does not manifest itself consistently and usually happens only at high doses. It can be comprehensively described through its variations as delirious in believability, autonomous in controllability and solid in style. They usually follow themes of memory replays and semi-realistic or expected events. For example, people could be casually holding objects or performing actions which one would expect them to be in real life before disappearing and dissolving under further inspection. Common examples of this include seeing people wearing glasses or hats when they are not and mistaking faces of your friends for random people, and objects as human beings or animals.

Internal hallucination - The internal hallucinations which 6-APB induce are mostly only present as spontaneous breakthroughs at extremely high doses. This effect's variations are delirious in believability, interactive in style, new experiences in content, autonomous in controllability and solid in appearance. The most common way in which they manifest themselves are through hypnagogic scenarios which the user may experience as they are drifting off to sleep after a night of use; these can usually be described as memory replay from the previous several hours. These are short and fleeting, but frequent and completely believable and convincing as they happen. In terms of the theme, they often take the form of conversations with the people who were with you or instead manifest themselves as bizarre and extremely nonsensical plots.

Cognitive effects

The cognitive effects of 6-APB can be broken down into several effects which progressively intensify proportional to dosage. The general head space of 6-APB is described by many as one of moderate mental stimulation, feelings of love, openness or empathy, and a powerful sense of contentedness and euphoria. It displays a large number of typical psychedelic, entactogenic and stimulant cognitive effects.
The most prominent of these cognitive effects generally include:

Cognitive euphoria - Strong emotional euphoria and feelings of happiness are present within 6-APB and are likely a direct result of serotonin and dopamine release.

Empathy, affection, and sociability enhancement - This particular effect is more consistent, pronounced, powerful and therapeutic with 6-APB than any other known substance. It is the most obvious and noticeable effect within any 6-APB experience and dominates the head space. With time, repeated use, and improper spacing, however, this effect becomes severely diminished as the perspective it instills becomes fully imprinted, making it, so users feel merely speedy and scattered with no new found urges to communicate or bond with others.

Memory suppression - This effect is thought to be mild in comparison with other substances such as alcohol, and classical benzodiazepines, lending to a more "spaced-out" feeling, best described as episodic memory.

Compulsive redosing - Due to its potential euphoria-inducing effects, there is the potential for 6-APB to encourage compulsive redosing, much like with MDMA or MDA. Due to the length of the experience, many find this need to be less pressing. Due to its unknown toxicity profile and reports of a severely amplified offset ("come down") and after effects, it is highly discouraged to redose this substance. It is thought to share some commonalities with DOM and other related compounds in this sense.

Auditory effects

Existential self-realization - Although this effect is present, it is not quite as pronounced or as consistent when compared to other hallucinogens such as mescaline, LSD or MXE. Due to the relative calmness and lack of chaotic energy that 6-APB possesses relative to MDMA, however, this combined with its extended duration may make it a better therapeutic agent and can be thought of as lying closer to the spectrum of mescaline than MDMA.

Unity and interconnectedness - While rare, experiences of unity, oneness and interconnectedness may occur on 6-APB. This effect most reliably manifests itself at high doses within large crowds at raves and musical events in the form of "becoming one with the crowd."

After effects

The effects which occur during the offset of a stimulant experience generally feel negative and uncomfortable in comparison to the effects which occurred during its peak. This is often referred to as a "comedown" and occurs because of neurotransmitter depletion. Its effects commonly include:

Toxicity and harm potential

Due to only having a short history of human use, the toxicity and harm potential is not exactly known. Due to its similarity to MDMA, it is likely that the administration of repeated or high dosages of 6-APB may be both neurotoxic and cardiotoxic[10][11] in some form.

The exact toxic dosage is unknown. It is strongly recommended that one use harm reduction practices when using this substance.

Short-term physical health risks of 6-APB consumption include dehydration, insomnia, and hyperthermia (overheating).[12] Continuous activity without sufficient rest or rehydration may cause body temperature to rise to dangerous levels, and loss of fluid via excessive sweating puts the body at further risk as the stimulating and euphoric properties of the substance may render the user oblivious to their energy expenditure for quite some time. Diuretics such as alcohol may exacerbate these risks further.

Although it has not been formally studied, small changes in ambient temperature may cause large changes in 6-APB-induced serotonergic neurotoxicity as is the case with MDMA.[13][14]

The neurotoxicity of 6-APB is subject to ongoing debate. It was specifically designed to be less neurotoxic than MDA or MDMA by circumventing the production of certain metabolic byproducts thought to underlie their toxicity (specifically alpha-methyl-dopamine).[citation needed] Although it is likely to be physically safe to try in a responsible context, it is completely possible that the administration of repeated or high dosages of 6-APB could result in neurotoxicity in some form, presenting as deficits in cognitive, affective and psychomotor function.

As with MDMA, the long-term, heavy usage of 6-APB (i.e. regular daily or weekly usage) is likely cardiotoxic and may lead to valvulopathy (heart valve issues) via its significant affinity for the 5-HT2B receptor.[15][16]

Tolerance and addiction potential

As with other stimulants, the chronic use of 6-APB can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal effects may occur if a person suddenly stops their usage.

As a potent releaser of serotonin, tolerance builds quickly with prolonged and repeated use to the point that the substance eventually loses any positive effects and instead leaves the user in an uncomfortable state of anxious, dysphoric stimulation. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3-4 weeks for the tolerance to be reduced to half and 6-8 weeks to be back at baseline (in the absence of further consumption). 6-APB presents cross-tolerance with all dopaminergicstimulants, meaning that after the consumption of 6-APB all stimulants will have a reduced effect.

Dangerous interactions

Although many psychoactive substances are safe to use on their own, they can quickly become dangerous or even life-threatening when combined with other substances. The following lists some known dangerous combinations, but may not include all of them. A combination that appears to be safe in low doses can still increase the risk of injury or death. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume.

Alcohol - Alcohol can be dangerous to combine with stimulants due to the risk of accidental over-intoxication. Stimulants mask the sedative effects of alcohol, which is the main factor people use to assess their degree of intoxication. Once the stimulant wears off, the depressant effects of alcohol are left unopposed, which can result in blackouts and respiratory depression. If combined, one should strictly limit themselves to only drinking a certain amount of alcohol per hour.

DXM - Combinations with DXM should be strictly avoided due to DXM's effects on serotonin and dopamine reuptake. This can lead to panic attacks, hypertensive crisis, or serotonin syndrome.

MXE - Combinations with MXE may dangerously elevate blood pressure and increase the risk of psychosis.

Tramadol - Tramadol lowers the seizure threshold.[17] Combinations with stimulants may further increase this risk.

There is an increased risk of serotonin syndrome when 6-APB is taken with many antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).[citation needed] Additionally, if 6-APB is taken with SSRIs and SNRIs, it is likely to be significantly less effective if it produces any discernible effects at all.

Legal status

Australia and New Zealand: Certain countries contain a "substantially similar" catch-all clause in their drug law, such as New Zealand and Australia. This includes 6-APB as it is similar in chemical structure to the class A drug MDA, meaning 6-APB may be viewed as a controlled substance analogue in these jurisdictions.[citation needed]

Canada: 6-APB is Schedule III in Canada as it is an analogue of MDA. The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1.[citation needed]

Sweden: 6-APB is prohibited in Sweden as a "health hazard" as of 2009.[citation needed]

United Kingdom: On June 10, 2013, 6-APB and some analogues were classified as Temporary Class Drugs in the U.K. following an ACMD recommendation. On March 5, 2014, the U.K. Home Office announced that 6-APB would be made a class B drug on 10 June 2014 alongside every other benzofuran entactogen and many structurally related drugs.[22]

United States: 6-APB is unscheduled in the United States, but not currently approved by the Food and Drug Administration for human consumption.[citation needed]